Rsks are a family of 90 kDa ribosomal S6 kinases, which are downstream effectors of MAPK; to date four isoforms have been identified.3 Recent studies have demonstrated the role of Rsk in cell survival signaling via the phosphorylation and inactivation of the pro-apoptotic protein BAD. Rsk has also been shown to directly promote cell survival by regulating the expression and activation of pro-survival proteins such as CREB (cyclic adenosine monophosphate response element binding protein).4 The combination of promoting cell survival and prevention of apoptosis causes excessive cell survival, eventually leading to diseases such as cancer and autoimmune disorders. Additionally, it has been found that Rsk2 is overexpressed in more than 50% of human breast cancers, validating the Rsk family as a potential target for drug design.
The overexpression of proteins in the mitogen-activated protein kinase (MAPK) pathway has been noted for a number of human malignancies,1 suggesting the possible utility of inhibitors of these proteins in cancer therapy. However, MAPK is involved in many fundamental cellular processes such as apoptosis, survival, differentiation, and proliferation.2 Consequently, the inhibition of protein mediators involved in multiple processes may result in effects on both normal and cancer cells in a nonselective manner. Logically, the identification of downstream mediators in the MAPK pathway essential for tumor growth might lead to inhibitors capable of selectively targeting cancer cells.
There is a long felt need in the art for methods of preparing and using inhibitors of p90Rsk which are useful for regulating cell proliferation and treating cancer. The present invention satisfies these needs.